The overall goal of this research program is to characterize the mechanisms and pathways that subvert cells from normal growth and differentiation to the transformed behaviors that occur in human cancer. The oncogenes and oncogenetic pathways in which they operate will be studied at the molecular, cellular and whole organism level, using mammalian cell lines, human cancer tissue, Drosophila and yeast as experimental systems. The research emphasis of the component projects are as follows: Subproject 0004 Broach will study ras- and Tor-mediated control of cell growth in response to nutrient availability, analyzing a key regulator (the protein phosphatase 2A/Tap42)- The two yeast signaling systems will serve as a model for how signaling imbalance causes tumorigenic transformation in larger cells. Subproject 0006 Schupbach will study the mechanisms that regulate activation of the Epidermal Growth Factor Receptor during Drosophila oogenesis, and will define the distinctive response pathways operating in different cell populations. Subproject 0009 Schwarzbaur and Notterman will use microarray technology to identify intracellular components controlling cell adhesion and integrin activity in fibrosarcomas, other human sarcomas, carcinomas and leukemias, as well as tissue arrays prepared from human tumor samples. Subproject 0007 Wieschaus and Cole will use Drosophila genetics and molecular biology to define interactions and cellular functions of beta-catenin, APC and two components of the Myc signal pathway (Tip 49 and 49), thought to interact with beta-catenin. Subproject 0010 Zakian, Shi and Singh propose a combined genetic, structural, and computational approach to characterize the Pifp1 subfamily of helicases, whose members have opposing effects on telomeric, mitochondrial and ribosomal DNA (rDNA). Perturbed maintenance of these DNAs has been correlated with tumorigenesis as well as aging.